Cardiac output (CO) and measures of cardiac preload (central blood volume, CBV) and systemic vascular resistance (SVR) are critical clinical parameters of circulatory function. The thermodilution technique is the accepted standard for measurement of CO. However, placement and maintenance of a pulmonary artery catheter required for such a measurement is technically challenging in neonates and infants and is associated with catheter-associated complications. Blood volume measurements can be performed quantitatively, however, these typically involve injection of radiolabelled tracers and/or extensive serial blood sampling and are infrequently performed. In fact, clinical decisions about the treatment of low perfusion states (shock) in these patients are currently being made based primarily on blood pressure and other indirect, fairly unreliable signs of tissue perfusion. These limitations have motivated studies of newer, less invasive techniques. We recently described a new indicator dilution method and instrumentation for assessing CO, circulating blood volume (BV), CBV, and SVR that is based on an intravenous bolus injection of the FDA-approved drug indocyanine green (ICG) and optical measurement of circulating blood ICG fluorescence. We now propose to develop and validate a skin probe, which can be used to measure cardiovascular parameters transcutaneously. The challenge is that skin perfusion is dynamic, which can affect the intensity of the fluorescence signal. We propose to account for this variability by designing a probe that combines the optical fluorescence measurements of circulating ICG with the measurement of local blood perfusion at the skin site using the well-established laser Doppler technique. This would allow us to adjust our fluorescence dye dilution signals to accurately derive CO, CBV, and SVR, irrespective of changes in local skin perfusion. Aim 1 is to develop and validate such a skin probe in a rabbit model. Aim 2 is to validate a clinical grade skin probe in adult subjects undergoing outpatient hemodialysis at the USC/DaVita Kidney Center. Aim 3 is to test the probe in neonates and infants in the Newborn and Infant Critical Care Unit at Children's Hospital Los Angeles and compare CO values with those obtained by functional echocardiography. Currently, a strong clinical need exists for a minimally invasive technique, which can provide rapid, serial measurements of cardiac function in neonates and infants. The proposed technique will lead to the development of a practical device for monitoring CO in minimally instrumented neonates in intensive care, operative and postsurgical settings, and in patients whose condition does not justify the use of central monitoring. This application is responsive to the NHLBI's research priority for improved technologies to image the heart (Task Force Report on Research in Pediatric Cardiovascular Disease, 2002), as well as the strategic priority (2009-2013) of the NCRR to incorporate innovations in biomedical technology into clinical research, and the NIBIB's Strategic Plan (2006) to foster interdisciplinary research for the accelerated translation of promising technologies to improve human health. PUBLIC HEALTH RELEVANCE: Currently, a strong clinical need exists for a minimally invasive technique, which can provide rapid, serial measurements of cardiac function and circulating blood volume in critically ill neonates and infants whose small body size renders more invasive methods (pulmonary artery thermodilution catheter) technically challenging and associated with significant risk. In fact, clinical decisions about the treatment of low perfusion states (shock) are currently being made based primarily on blood pressure and other indirect, fairly unreliable signs of tissue perfusion. Our proposal addresses this need with the development and validation of an optical probe, which can be used to measure cardiac function through the skin for applications in neonatal critical care and in patients whose condition does not justify the use of more invasive monitoring.